Int. J. Rodiation
Oncology
Biol.
Phys.,
1977, Vol.
2, pp. 537-548.
Pergamon
Press.
Printed in tk
U.S.A.
??Brief Communication
ONCE A WEEK TREATMENTS FRANK ELLIS, M.D. and ALFRED L. GOLDSON, M.D. Memorial Sloan Kettering Cancer Center, Department of Radiotherapy, 1275 York Avenue NY 10021, U.S.A. In 35 cancer patients who were treated from 1974 through June lW6, once a week treatments (e.g. 7 thnes 615 rad = 4305 rad = 1800 ret) were tolerated as wel1 snd seemed to produce at least as good results as treatments with 4-5 fractions per week. One treatment per week has obvious practical advantages for the non-hospitaiized patient and for a busy department. Once a week fractionation,
Single high dose radiation fractionation, NSD: correlations with single high dose fractionation, Tumor response to non-conventionai fractionation.
INTRODUCTION
Many fractionation schedules have been employed in teletherapy. The early German practice was to give the whole dose at one time. The French school under Regaud’ established by careful clinical observation, that better results were obtained by fractionating the total dose in many treatments over several weeks. With treatments “never on Sunday ,” this led to 6 treatments per week. With introduction of long weekends, 5 treatments per week became the standard schedule. A 4 treatment per week schedule resulted when Wednesday was kept free; this has become the first choice of some departments for outpatients. Many radiotherapists also have used 3 treatments per week and 2 treatments per week. At the other end of the with 2 and spectrum, “superfractionation” more fractions per day as wel1 as continuous teletherapy radiation also is being tried. By decreasing or increasing the size of each fraction, further modifications are possible. Recent conferences devoted to the question of optimal fractionation were held in Kyoto, Japan, 1972 (The Size of Individual Reprint requests to: Dr. Frank Ellis, Cancer Institute of New Jersey, 145 Roseville Avenue,
Dose Fractions in Radiobiology and Radiotherapy),” and at the University of Wisconsin, 1975 (Time-Dose Relationship in Clinical Radiotherapy).’ The detailed conference reports on these meetings vividly demonstrate the uncertainties and the wide differences in clinical practice and in radiobiological theory. Despite the great interest in fractionation, one treatment per week has not been tried systematically. One treatment per week is one of the most convenient schedules for most patients who do not have to be hospitalized or who live at a distance. A weekly visit to the radiotherapy department usually can be arranged without upsetting his life and work schedule. If the patient needs assistance or transportation, it usually is easy to find a friend, relative or agency, who can bring the patient once a week. Obviously, 1 treatment per week can be recommended only if it produces approximately the same results as the commonly used multiple treatments per week. In this paper we report a smal1 series of 35 patients, Newark, 531
treated
with
1 treatment
NJ 07107, U.S.A.
per week,
Squamous Squamous Basal Cel1 Ca.
63WM 63WM
62WF
65WF 79WM
30WM
62WM 27WM 55WF
75WF 66WF
54WM
51WM
10 11
12
13 14
15
16 17 18
19 20
21
22
Ca. Ca.
Ca.
Adenocarcinoma
Adenocarcinoma colon
Melanoma Melanoma
Melanoma Melanoma Melanoma
Melanoma
Basal Cel1 Ca. Basal Cel1 Ca.
Squamous
83WF
9
Ca.
Squamous
62WM
8
Ca. Ca. Ca. Ca. Ca. Ca. Ca.
Squamous Squamous Squamous Squamous Squamous Squamous Squamous
65WM 71WF 77WF 83WF 68WM 82WM
1 2 3 4 5 6 7
Histology
Age, race and sex
P atient
Table 1. Results in al1 patients
mass/7 cm4
Rt. main stem bronchus mets from colon Prostate
Skin rt. neck/l2cm+ Left foot/7 cm+
Lt. ant. chest/5 cm+ Iliac fossa/8 cm4 Rt. leg/75 cm
Lt. neck
Lt. side face 15x8cm2 Nose/7 x 6 cm2 Right nose/3 cm4
+++
++
0 on 1/4 complete
+++ + +
++++
++++ NED ++++NED ++++NED
++++ Left malar region nose/2 cm4 NED Left and Right ++ inguinals and vulva Face and neck ++++NED Left neck/ll x 10 cm* +
7 x 615 5 x 690
8x600
7x650 10 x 575
6X600 7 x 630
7 x 615 5x355 8x700 7x600 7x615 12x400 1x850 4x655
Fractions rad/fract.
NY, 1974-76
6X610 1x500 6 x 570
6x600 2x300 7 x 550 9x500 3 x 624 6X600 then 120 rad 3xlday x 10 days 8x615 2 x 650
Center,
Lung, Med./lO4S + Chest WaI1/18+ + Ant. Neck/lS x 10cm’ + + + + NED* Lower Leg/ 124 +++ Anus/12 x 6 cm* ++ Lung, Med./6 cm4 +++ Buccal Mucosaló cm4 +++
Response
once weekly at the Memorial
Locationlsize
treated
36
36
60 14
40 64 73
59
64 29
51
57 52
50 45
58 59 50 42 79 46 42
Time days
1500
1696
2057 563
1584
1500 1700 780 1500
1746
1800 1800
1972
1900 2190
1500 1853
1800 1679 2200 1740 1800 1770 1517
Ret
70WF
27WF 59WF
20WM 23WF 44WF 63WF
20WF
66WM
52BF
50WM
81WF
24
25 26
27 28 29 30
31
32
33
34
35 Schwannoma
Schwannoma
Schwannoma
Schwannoma
Schwannoma
Sarcoma Sarcoma Sarcoma Sarcoma
Adenocarcinoma Adenocarcinoma
Adenocarcinoma
Adenocarcinoma
ulna mets knee post op buttock humerus
Lt. sacrum and hip
Lt. side of head/l5 cmd Rt. hemi-abdomen/ 30 X 17 cm2 Rt. dosum foot//6 cm& Rt & Lt neck/l5 cm4
Lt. Rt. Rt. Rt.
Lt. neck parotid Lt. ant. chest breast 1”
Lt. supraclavicular breast 1” Lt. frontal parietal skull from breast 1”
tNo evidente of disease. $4 = greatest diameter of measurable tumor. Nute. Criteria for tumor response are listed in Table 3.
59WF
23
++
++++ +
+++
+++
+++ ++++NED ++++NED +
++
subct. mets+ + + bone mets + +
+++
7 x 585 2x596 4x615 6x508 1 x 600
7 x 565
7x505
7 x 650 8x565 6 x 620 4x585
17 x 300 2xlwk
3 x 565
5 x 680
4x615
50
78 51
82
43
44 57 42 22
54
15
30
22
1384
1632 1470
1450
1700
1900 1800 1565 900
1590
675
1600
1250
Radiation Oncology 0 Biology 0 Physics
540
who seem to have done surprisingly well. We also wil1 present theoretical considerations, which raise the possibility that some tumors might respond better to once a week treatments than to more conventional schedules METHODS AND MATERIALS Ma terials
Our first patients treated with a once weekly schedule were patients of the senior author while he was at Oxford University in England and at the Milwaukee County Medical Complex and the Medical College of Wisconsin, in Milwaukee. These patients had favourable, easily observable skin lesions, and the good long term results without undue damage to normal tissues inspired the present study. In 1974 we began a study of once a week treatments at the Memorial Center for Cancer in New York City. Until June 1976, when both authors left the Memorial Center, 35 patients were entered. We have tried to observe the tumor response and the normal tissue reactions in these patients as accurately and scientifically as possible. We are providing the details of these observations in as much detail as possible, to let other radiotherapists judge for themselves the potential of radiotherapy given in weekly fractions. The age, sex, histology and anatomical location of the tumors of our patients are detailed in Table 1. Many of our 35 patients were failures after surgery and chemotherapy and most had far advanced cancer.
May-June 1977, Volume 2, No. 5 and No. 6
covering the affected skin with bolus material if high energy photons (“Co or linear accelerators) were used. For deep lesions, the dose distribution was properly planned and whenever possible, checked with thermoluminescent dosimeters. The total dose was guided by the data given in Table 2. They are based on the NSD formula D = NSD x T’.” x N”.24, where D is the total dose in rad, NSD the “tolerante dose in ret,” T the overall time of the treatment in days and N the number of fractions.2-8 The table gives the dose per fraction in rad for once weekly treatments for ?Zo and other supervoltage radiation for 5, 6, 7 and 8 fractions and for ret values of 1800, 1900 and 2000ret. For the commonly used dose of 1800 ret, for instance, 5 treatments of 700 rad = 3500 rad total, or 6 treatments of 680rad = 4800rad total, or 7 treatments of 615rad = 4305, or 8 treatments of 565rad = 4520 rad total would be required. In this series a dose of 1800ret was used in most cases. We realize that 1900ret or even 2000 ret may be desirable so as to approach a higher probability of cure. Our criteria for response are based on measured regression of the treated lesion (Table 3). We distinguish four degrees of re-
Table 3. Criteria for tumor response % of original diameter
Regression of tumor + ++ +++ ++++ NED
Methods
In al1 patients the treatment plan was to give a uniform dose to the tumor volume. In lesions involving the skin, electron beams were used or build up was achieved by
75 50 25 0 NO evidente of disease
Table 2. Rad per fraction for once weekly treatment for 1800, 1900 and 2000ret for “Co and supervoltage Equivalent dose
TDF-ì
5
1800 ret 1900 ret 2000 ret
102 108 112
700 rad 800 rad 81.5rad
radiation
Number of fractions 6 7
tTDF = Time, Dose, Fractionation.
680 rad 710 rad 720rad
615 rad 640 rad 655 rad
8 565 rad 595 rad 600rad
Once
a week
treatments
541
0 F. ELLIS and A. L. GOLDSON
skin grafts. Large ulcerated lesions, although they might eventually heal by themselves, are managed more speedily with a skin graft. It should be applied soon after the radiation treatment, while the blood supply is stil1 intact. Chemotherapy was not used during the treatment of these patients.
sponse; namely +, ++, +++ and ++++, which denote at least 75%, 50%, 25% and 0% of original tumor diameter. These decreases in diameter correspond to 40%, 12%, 1.5% and 0% of the o’riginal tumor volume. To be scored the regression must have persisted at least 3 months or until death. When the treated tumor had disappeared entirely and no metastases were present at follow up, NED (NO Evidente of Disease) was added to response. In two cases of extensive skin lesions, supplementary therapy was given by split
As illustrative cases, two patients with basal cel1 carcinoma, one patient with a metastatic malignant melanoma and one pa-
(4
(bl
Fig. 1. 600 rad
RJISULTS
(4 Response of basal cel1 carcinoma to once weekly treatments. (Patient (1600 ret); (a) Before radiation; (b) Post radiation; (c) Skin graft post radiation; year
post radiation
and graft.
1)
8x (d) 1
542
Radiation Oncology 0 Biology 0 Physics
tient with malignant Schwannoma are discussed. Patient 1. C.L. This 62 year old female had noticed an increasing ulceration of the left side of her face for more than 10 years. In January, 1975 a biopsy revealed basal cel1 carcinoma. From 2 April 1975 to 22 May 1975 she received once weekly treatment with a total of 4800rad to the left side of her face. Betatron 8 MeV electrons were used in 8 fractions of 600 rad calculated at the 90% isodose leve1 through a lead mask. After radiation she received a skin graft to the left side of her face. In June 1976 there was no evidente of disease (Fig. 1). Patient 2. M.M. This 71 year old female presented on 3 May 1975 with a 9 year history of a lesion involving both upper eyelids and both sides of the nose. Biopsy showed basal cel1 carcinoma. From 13 May 1975 to 15 July 1975 she received once weekly treatment with 6 fractions of 615 rad each for a total of 3840 rad. Betatron electrons of 8 MeV were used. On 16 August 1975 an (Ir) 192 removable implant was carried out to her forehead and check. On 18 September 1975
May-June 1977, Volume 2, No. 5 and No. 6
she received an additional one time treatment of 615 rad to her anterior right nasolabial fold and to her forehead. On examination on 10 November 1975 and on 5 February 1976 she had slight telangectasis, but no evidente of disease (Fig. 2). Patient 3. F. W. This 56 year old female had a 7 year history of recurrent malignant melanoma of the left thigh. Initial treatment elsewhere in 1969 was wide surgical excision of the primary with in-continuity left groin dissection with skin graft. In April 1975 she presented with a recurrence in the same region. Biopsy taken from the left thigh, on 10 April 1974 showed malignant melanoma present in dermis and fat. Chest X-ray revealed pulmonary metastases; for this she was started on Dacarbazine and Vincristine. She was seen again at Memorial Hospita1 on 16 October 1975 with a large 10 x 8 cm* mobile tumor of the left inner thigh and was started on once a week radiation therapy. From 16 October 1975 to 6 January 1976, 4760rad was given in 7 fractions of 680rad by 8 MeV Betatron electrons. A repeat biopsy on 16 February 1976, 2 months post therapy of the
(4 (b) Fig. 2. Response of a basal cel1 carcinoma to once weekly treatments. (Patient 2) 6 x 615 rad plus 19*Irimplant and boost of 1 x 615 (1760 ret); (a) Before radiation; radiation.
(b) 6 months post
Once a week treatments 0 F. ELLISand A. L. GOLDSON
Fig. 3. Response of a malignant melanoma to once weekly treatments. (Patient 3) 7 x 680 rad (1980ret); (a) Before radiation; (b) 4.5 months post radiation.
same area showed persistent malignant melanoma in fibrous tissue. However on 20 April 1976,4.5 months post irradiation, biopsy showed only fibrous connective tissue with abundant melanotic pigment but no melanoma cells. (Figs. 3, 4). Patient 4. M.P. This 20 year old female had neurofibromatosis since childhood. She was admitted to the Memorial Center on 17 July 1974, with a rapidly enlarging 8 x 10 x 6 cm3 firm left neck mass and pain, which on biopsy proved to be a malignant Schwannoma. Excision of the vascular lesion from the left side of the neck and elective tracheostomy were performed on 31 July 1974. From August 1974 to September 1974, she received chemotherapy. Then she was referred for emergency treatment to the radiotherapy department, because the tumor was growing rapidly. Significant regression of the tumor occurred after the first treatment. As of 11 October 1974, she had received a total dose of 4550 rad by wedge fields with wax bolus to
left neck and tempora1 region in 7 fractions of 650rad per week for 1840ret. The patient died on 10 January 1975 at another hospita1 with intracranial extension. The treated tumor had regressed significantly before death, as can be seen from the photographs. (Fig. 5.) The majority of patients (97%) showed at least a 25% regression to once a week treatments. Only 1 melanoma patient showed no response. In 11 of 35 patients (31%) complete regression of the treated lesions occurred. The difficulties to compare these results to historical controls are, of course, too wel1 known to merit discussion here, and obviously one cannot draw far reaching conclusions from this relatively smal1 number of patients. However, we would like to record that the response of this group of tumors to once weekly treatments seemed to be distinctly better than we had anticipated on the basis of our experience with radiotherapy with multiple fractions per week. This subjective clinical judgement must be substan-
544
Radiation
Oncology
0 Biology
0 Physics
May-June
Fig. 4(a).
1977, Volume
2, No. 5 and No. 6
Once a week treatments
0 F. ELLISand A. L. GOLDSON
Fig. 4(b).
545
546
Radiation
Oncology
0 Biology
0 Physics
May-June
1977, Volume
2, No. 5 and No. 6
Fig. 4(c). Fig. 4. Histological response of a malignant melanoma to once weekly treatments. (Patient 3);( a) Original biopsy: melanoma present in dermis and fat; (b) Two months post radiation; pers ;istent melanoma in dense fibrous tissue; (c) 4.5 months post radiation: abundant fibrous connective tissue with melanotic pigment but no malignant cells.
Once a week treatments 0 F. ELLIS and A. L. GOLDSON
(al
(bl
Fig. 5. Response of a malignant Schwannoma to once weekly treatments. (Patient 7 X 650 rad (1840 ret); (a) Before radiation; (b) Two months post radition.
tiated in the future by large numbers of patients, by a greater variety of tumors and if possible by prospective clinical trial. In the 35 patients treated at Memorial by this fractiohation schedule, the ret dose ranged from a low of 563 to 2190ret. Careful follow up of these 35 patients revealed mild and transient symptomatology, such as erythema, tanning, diarrhea and telangiectasia in approximately 50% of cases, but no severe morbidity or mortality attributable to radiation with 1800 ret was encountered. We admit that our follow up period is short, with maximum follow up period approaching only 2 years. DISCUSSION Radiotherapy once a week clearly is a most attractive time schedule, if it can be shown that the results are as good as those with multiple fractions per week. It permits the cancer patient who does not have to be hospitalized and who lives within commuting distance to go on without interrupting his life and work schedule and at the same time to get the medical care and supervision he needs for proper cancer management. Few cancer patients who are undergoing radiation therapy need a medical examination including blood counts more than once a week. The advantages of once a week treatments
547
are so obvious
4)
in some situations, that this schedule has been used on occasion by a number of radiotherapists. For instance at Ohio State University Hospita1 Henschke treated 30 patients in the years 1952-55 with 500 rad per week for a total dose of 5000 rad. (Personal Communication oral, October 1976.) These were patients from outlying farms in Ohio, who could not come or could not be brought for radiotherapy more often. The response seemed to be essentially the same as with conventional fractionation. Aristizabal’ reported from Columbia, South America that with only one cobalt machine for 3 million people, treatments of 500 rad given once a week made it possible to treat many patients, who otherwise would have gone untreated. He also stated, that at the Puerto Rico Nuclear Center, 38 cases of advanced carcinoma of the breast have been treated with once a week doses of 500 rad for a total of 5000 rad with satisfactory response.’ The most facinating implication of our data is the possibility, that at least for some tumors, once a week treatment may be better than multiple fractions per week. This possibility rarely has been considered, but it is by no means a radiobiological impossibility. It has been suggested previously by Ellis that for cells with higher extrapolation num-
548
Radiation Oncology 0 Biology 0 Physics
bers a smal1 number of large fractions may, for the same NSD, leave fewer survivors than wil1 the conventional 30 doses of 200rad. Moreover, it appeared that for cells with extrapolation numbers of 2, such as connective tissue a smal1 number of large fractions might have a smaller effect than the conventional30 x 200 rad. As has been shown by Ellis and Sorenson,2.3 the graphs of cel1 survival and ret are almost coincident if numbers of fractions are plotted against dose per fractions for D,, = 160 n = 2 or Do = 150 n = 2.2. In other words, a smal1 number of large dose fractions have in the NSD concept the same cell-killing effect on the normal connective tissue as conventional fractionation, but a greater cell-killing effect on cells with high extrapolation numbers, such as seem to be characteristic of resistant tumors. Conceptually it seems reasonable (if malignant cells are dividing slowly and die only as a result of radiation in subsequent mitoses), to allow time between fractions for proliferation of normal cells. Their growth may be aided by homoeostatic recovery processes and by improved oxygenation, which leave gaps in the tumor because of
May-June lW7, Volume 2, No. 5 and No. 6
gradual autolysis of the destroyed malignant cells. In this connection, it also is interesting that recent skin erythema studies on patients by Turesson and Natter” showed that the radiation reactions of the normal skin were identical after 5 treatments per week with 235 rad each for a total of 3760rad in 16 treatments in 22 days (1400 ret) and after irradiation once a week with 675 rad for a total of 2700 rad in 4 treatments in 22 days (1400 ret). Finally, we would like to reflect, that widely different time and dose schedules have shown in clinical practice only such smal1 differences in tumor control and normal tissue damage, that no schedule has emerged, which clearly is superior. If different schedules give essentially the same results, one should pick the one which is more convenient for the patient and which permits to take care of more patients in the areas of the world, which lack radiation therapists and supervoltage machines. Once a week treatments thus could become a significant contribution to practica1 cancer management.
REFERENCES 1. Aristizabal, S.: Discussion remarks. In Proc. radiotherapy. Front. Rad. Ther., Vol. 3, ed. by Conf. on the Time-dose Relationship in CliniVaeth, J.M. Karger, Basel, 1968, pp. 131-140. cal Radiotherapy, ed. by Caldwell W.L., Tol7. Ellis, F.: Fractionation in radiotherapy. In bert D.D. Middleton, Wisconsin, Madison Modem Trends in Radiotherapy, ed. by Printing & Publishing, 1975, p. 189. Seeley, T.J., Wood, C.A. London, Butter2. Ellis, F., Sorensen, A.: A method of estimating worths, 1967, Chap. 2, pp. 34-51. biological effect of combined intracavitary low 8. Ellis, F.: Tolerante dosage in radiotherapy dose rate radiation with external in carcinoma of with 200KV X-rays. Br. J. Radiol. 15: 348, the cervix uteri. Radiology 110-681, 1974. 1942. 3. Ellis, F.: Letter: The NSD concept and 9. Regaud, C.: Influence de la duree d’irradiation Br. J. Radiol. 47 sur les effects determines dans le testicule par radioresistant tumors. (564) p. 909, 1974. le radium. Compt. Rend Sec. de Biol. 86: 7874. Ellis, F.: Nomina1 standard dose and the ret. 790, 1922. Br. J. Radiol. 44: 101-108, 1971. 10. Sugahara, T., Revesz, L., Scott, 0. (eds): 5. Ellis, F.: The relationship of biological effect Fraction Size in Radiobiology, Tokyo, Igaku to dose-time fractionation factors in radioShoin, 1973, pp. 180-187. Radiation ll. Turesson I., Notter, G.: Control of dose adtherapy. Topics in Current ministered once a week and three times a day Research, Vol. 4, ed. by Ebert, M., Howard, J. H. Amsterdam, North-Holland, 1968, Chap. 7, according to schedules calculated by the CRE formula, using skin reaction as a biological pp. 359-397. 6. Ellis, F.: Time, fractionation and dose rate in parameter. Radiology 120: 339404, 1976.
Oncology
Biol.
Phys.,
1977, Vol.
2, pp. 537-548.
Pergamon
Press.
Printed in tk
U.S.A.
??Brief Communication
ONCE A WEEK TREATMENTS FRANK ELLIS, M.D. and ALFRED L. GOLDSON, M.D. Memorial Sloan Kettering Cancer Center, Department of Radiotherapy, 1275 York Avenue NY 10021, U.S.A. In 35 cancer patients who were treated from 1974 through June lW6, once a week treatments (e.g. 7 thnes 615 rad = 4305 rad = 1800 ret) were tolerated as wel1 snd seemed to produce at least as good results as treatments with 4-5 fractions per week. One treatment per week has obvious practical advantages for the non-hospitaiized patient and for a busy department. Once a week fractionation,
Single high dose radiation fractionation, NSD: correlations with single high dose fractionation, Tumor response to non-conventionai fractionation.
INTRODUCTION
Many fractionation schedules have been employed in teletherapy. The early German practice was to give the whole dose at one time. The French school under Regaud’ established by careful clinical observation, that better results were obtained by fractionating the total dose in many treatments over several weeks. With treatments “never on Sunday ,” this led to 6 treatments per week. With introduction of long weekends, 5 treatments per week became the standard schedule. A 4 treatment per week schedule resulted when Wednesday was kept free; this has become the first choice of some departments for outpatients. Many radiotherapists also have used 3 treatments per week and 2 treatments per week. At the other end of the with 2 and spectrum, “superfractionation” more fractions per day as wel1 as continuous teletherapy radiation also is being tried. By decreasing or increasing the size of each fraction, further modifications are possible. Recent conferences devoted to the question of optimal fractionation were held in Kyoto, Japan, 1972 (The Size of Individual Reprint requests to: Dr. Frank Ellis, Cancer Institute of New Jersey, 145 Roseville Avenue,
Dose Fractions in Radiobiology and Radiotherapy),” and at the University of Wisconsin, 1975 (Time-Dose Relationship in Clinical Radiotherapy).’ The detailed conference reports on these meetings vividly demonstrate the uncertainties and the wide differences in clinical practice and in radiobiological theory. Despite the great interest in fractionation, one treatment per week has not been tried systematically. One treatment per week is one of the most convenient schedules for most patients who do not have to be hospitalized or who live at a distance. A weekly visit to the radiotherapy department usually can be arranged without upsetting his life and work schedule. If the patient needs assistance or transportation, it usually is easy to find a friend, relative or agency, who can bring the patient once a week. Obviously, 1 treatment per week can be recommended only if it produces approximately the same results as the commonly used multiple treatments per week. In this paper we report a smal1 series of 35 patients, Newark, 531
treated
with
1 treatment
NJ 07107, U.S.A.
per week,
Squamous Squamous Basal Cel1 Ca.
63WM 63WM
62WF
65WF 79WM
30WM
62WM 27WM 55WF
75WF 66WF
54WM
51WM
10 11
12
13 14
15
16 17 18
19 20
21
22
Ca. Ca.
Ca.
Adenocarcinoma
Adenocarcinoma colon
Melanoma Melanoma
Melanoma Melanoma Melanoma
Melanoma
Basal Cel1 Ca. Basal Cel1 Ca.
Squamous
83WF
9
Ca.
Squamous
62WM
8
Ca. Ca. Ca. Ca. Ca. Ca. Ca.
Squamous Squamous Squamous Squamous Squamous Squamous Squamous
65WM 71WF 77WF 83WF 68WM 82WM
1 2 3 4 5 6 7
Histology
Age, race and sex
P atient
Table 1. Results in al1 patients
mass/7 cm4
Rt. main stem bronchus mets from colon Prostate
Skin rt. neck/l2cm+ Left foot/7 cm+
Lt. ant. chest/5 cm+ Iliac fossa/8 cm4 Rt. leg/75 cm
Lt. neck
Lt. side face 15x8cm2 Nose/7 x 6 cm2 Right nose/3 cm4
+++
++
0 on 1/4 complete
+++ + +
++++
++++ NED ++++NED ++++NED
++++ Left malar region nose/2 cm4 NED Left and Right ++ inguinals and vulva Face and neck ++++NED Left neck/ll x 10 cm* +
7 x 615 5 x 690
8x600
7x650 10 x 575
6X600 7 x 630
7 x 615 5x355 8x700 7x600 7x615 12x400 1x850 4x655
Fractions rad/fract.
NY, 1974-76
6X610 1x500 6 x 570
6x600 2x300 7 x 550 9x500 3 x 624 6X600 then 120 rad 3xlday x 10 days 8x615 2 x 650
Center,
Lung, Med./lO4S + Chest WaI1/18+ + Ant. Neck/lS x 10cm’ + + + + NED* Lower Leg/ 124 +++ Anus/12 x 6 cm* ++ Lung, Med./6 cm4 +++ Buccal Mucosaló cm4 +++
Response
once weekly at the Memorial
Locationlsize
treated
36
36
60 14
40 64 73
59
64 29
51
57 52
50 45
58 59 50 42 79 46 42
Time days
1500
1696
2057 563
1584
1500 1700 780 1500
1746
1800 1800
1972
1900 2190
1500 1853
1800 1679 2200 1740 1800 1770 1517
Ret
70WF
27WF 59WF
20WM 23WF 44WF 63WF
20WF
66WM
52BF
50WM
81WF
24
25 26
27 28 29 30
31
32
33
34
35 Schwannoma
Schwannoma
Schwannoma
Schwannoma
Schwannoma
Sarcoma Sarcoma Sarcoma Sarcoma
Adenocarcinoma Adenocarcinoma
Adenocarcinoma
Adenocarcinoma
ulna mets knee post op buttock humerus
Lt. sacrum and hip
Lt. side of head/l5 cmd Rt. hemi-abdomen/ 30 X 17 cm2 Rt. dosum foot//6 cm& Rt & Lt neck/l5 cm4
Lt. Rt. Rt. Rt.
Lt. neck parotid Lt. ant. chest breast 1”
Lt. supraclavicular breast 1” Lt. frontal parietal skull from breast 1”
tNo evidente of disease. $4 = greatest diameter of measurable tumor. Nute. Criteria for tumor response are listed in Table 3.
59WF
23
++
++++ +
+++
+++
+++ ++++NED ++++NED +
++
subct. mets+ + + bone mets + +
+++
7 x 585 2x596 4x615 6x508 1 x 600
7 x 565
7x505
7 x 650 8x565 6 x 620 4x585
17 x 300 2xlwk
3 x 565
5 x 680
4x615
50
78 51
82
43
44 57 42 22
54
15
30
22
1384
1632 1470
1450
1700
1900 1800 1565 900
1590
675
1600
1250
Radiation Oncology 0 Biology 0 Physics
540
who seem to have done surprisingly well. We also wil1 present theoretical considerations, which raise the possibility that some tumors might respond better to once a week treatments than to more conventional schedules METHODS AND MATERIALS Ma terials
Our first patients treated with a once weekly schedule were patients of the senior author while he was at Oxford University in England and at the Milwaukee County Medical Complex and the Medical College of Wisconsin, in Milwaukee. These patients had favourable, easily observable skin lesions, and the good long term results without undue damage to normal tissues inspired the present study. In 1974 we began a study of once a week treatments at the Memorial Center for Cancer in New York City. Until June 1976, when both authors left the Memorial Center, 35 patients were entered. We have tried to observe the tumor response and the normal tissue reactions in these patients as accurately and scientifically as possible. We are providing the details of these observations in as much detail as possible, to let other radiotherapists judge for themselves the potential of radiotherapy given in weekly fractions. The age, sex, histology and anatomical location of the tumors of our patients are detailed in Table 1. Many of our 35 patients were failures after surgery and chemotherapy and most had far advanced cancer.
May-June 1977, Volume 2, No. 5 and No. 6
covering the affected skin with bolus material if high energy photons (“Co or linear accelerators) were used. For deep lesions, the dose distribution was properly planned and whenever possible, checked with thermoluminescent dosimeters. The total dose was guided by the data given in Table 2. They are based on the NSD formula D = NSD x T’.” x N”.24, where D is the total dose in rad, NSD the “tolerante dose in ret,” T the overall time of the treatment in days and N the number of fractions.2-8 The table gives the dose per fraction in rad for once weekly treatments for ?Zo and other supervoltage radiation for 5, 6, 7 and 8 fractions and for ret values of 1800, 1900 and 2000ret. For the commonly used dose of 1800 ret, for instance, 5 treatments of 700 rad = 3500 rad total, or 6 treatments of 680rad = 4800rad total, or 7 treatments of 615rad = 4305, or 8 treatments of 565rad = 4520 rad total would be required. In this series a dose of 1800ret was used in most cases. We realize that 1900ret or even 2000 ret may be desirable so as to approach a higher probability of cure. Our criteria for response are based on measured regression of the treated lesion (Table 3). We distinguish four degrees of re-
Table 3. Criteria for tumor response % of original diameter
Regression of tumor + ++ +++ ++++ NED
Methods
In al1 patients the treatment plan was to give a uniform dose to the tumor volume. In lesions involving the skin, electron beams were used or build up was achieved by
75 50 25 0 NO evidente of disease
Table 2. Rad per fraction for once weekly treatment for 1800, 1900 and 2000ret for “Co and supervoltage Equivalent dose
TDF-ì
5
1800 ret 1900 ret 2000 ret
102 108 112
700 rad 800 rad 81.5rad
radiation
Number of fractions 6 7
tTDF = Time, Dose, Fractionation.
680 rad 710 rad 720rad
615 rad 640 rad 655 rad
8 565 rad 595 rad 600rad
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skin grafts. Large ulcerated lesions, although they might eventually heal by themselves, are managed more speedily with a skin graft. It should be applied soon after the radiation treatment, while the blood supply is stil1 intact. Chemotherapy was not used during the treatment of these patients.
sponse; namely +, ++, +++ and ++++, which denote at least 75%, 50%, 25% and 0% of original tumor diameter. These decreases in diameter correspond to 40%, 12%, 1.5% and 0% of the o’riginal tumor volume. To be scored the regression must have persisted at least 3 months or until death. When the treated tumor had disappeared entirely and no metastases were present at follow up, NED (NO Evidente of Disease) was added to response. In two cases of extensive skin lesions, supplementary therapy was given by split
As illustrative cases, two patients with basal cel1 carcinoma, one patient with a metastatic malignant melanoma and one pa-
(4
(bl
Fig. 1. 600 rad
RJISULTS
(4 Response of basal cel1 carcinoma to once weekly treatments. (Patient (1600 ret); (a) Before radiation; (b) Post radiation; (c) Skin graft post radiation; year
post radiation
and graft.
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8x (d) 1
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tient with malignant Schwannoma are discussed. Patient 1. C.L. This 62 year old female had noticed an increasing ulceration of the left side of her face for more than 10 years. In January, 1975 a biopsy revealed basal cel1 carcinoma. From 2 April 1975 to 22 May 1975 she received once weekly treatment with a total of 4800rad to the left side of her face. Betatron 8 MeV electrons were used in 8 fractions of 600 rad calculated at the 90% isodose leve1 through a lead mask. After radiation she received a skin graft to the left side of her face. In June 1976 there was no evidente of disease (Fig. 1). Patient 2. M.M. This 71 year old female presented on 3 May 1975 with a 9 year history of a lesion involving both upper eyelids and both sides of the nose. Biopsy showed basal cel1 carcinoma. From 13 May 1975 to 15 July 1975 she received once weekly treatment with 6 fractions of 615 rad each for a total of 3840 rad. Betatron electrons of 8 MeV were used. On 16 August 1975 an (Ir) 192 removable implant was carried out to her forehead and check. On 18 September 1975
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she received an additional one time treatment of 615 rad to her anterior right nasolabial fold and to her forehead. On examination on 10 November 1975 and on 5 February 1976 she had slight telangectasis, but no evidente of disease (Fig. 2). Patient 3. F. W. This 56 year old female had a 7 year history of recurrent malignant melanoma of the left thigh. Initial treatment elsewhere in 1969 was wide surgical excision of the primary with in-continuity left groin dissection with skin graft. In April 1975 she presented with a recurrence in the same region. Biopsy taken from the left thigh, on 10 April 1974 showed malignant melanoma present in dermis and fat. Chest X-ray revealed pulmonary metastases; for this she was started on Dacarbazine and Vincristine. She was seen again at Memorial Hospita1 on 16 October 1975 with a large 10 x 8 cm* mobile tumor of the left inner thigh and was started on once a week radiation therapy. From 16 October 1975 to 6 January 1976, 4760rad was given in 7 fractions of 680rad by 8 MeV Betatron electrons. A repeat biopsy on 16 February 1976, 2 months post therapy of the
(4 (b) Fig. 2. Response of a basal cel1 carcinoma to once weekly treatments. (Patient 2) 6 x 615 rad plus 19*Irimplant and boost of 1 x 615 (1760 ret); (a) Before radiation; radiation.
(b) 6 months post
Once a week treatments 0 F. ELLISand A. L. GOLDSON
Fig. 3. Response of a malignant melanoma to once weekly treatments. (Patient 3) 7 x 680 rad (1980ret); (a) Before radiation; (b) 4.5 months post radiation.
same area showed persistent malignant melanoma in fibrous tissue. However on 20 April 1976,4.5 months post irradiation, biopsy showed only fibrous connective tissue with abundant melanotic pigment but no melanoma cells. (Figs. 3, 4). Patient 4. M.P. This 20 year old female had neurofibromatosis since childhood. She was admitted to the Memorial Center on 17 July 1974, with a rapidly enlarging 8 x 10 x 6 cm3 firm left neck mass and pain, which on biopsy proved to be a malignant Schwannoma. Excision of the vascular lesion from the left side of the neck and elective tracheostomy were performed on 31 July 1974. From August 1974 to September 1974, she received chemotherapy. Then she was referred for emergency treatment to the radiotherapy department, because the tumor was growing rapidly. Significant regression of the tumor occurred after the first treatment. As of 11 October 1974, she had received a total dose of 4550 rad by wedge fields with wax bolus to
left neck and tempora1 region in 7 fractions of 650rad per week for 1840ret. The patient died on 10 January 1975 at another hospita1 with intracranial extension. The treated tumor had regressed significantly before death, as can be seen from the photographs. (Fig. 5.) The majority of patients (97%) showed at least a 25% regression to once a week treatments. Only 1 melanoma patient showed no response. In 11 of 35 patients (31%) complete regression of the treated lesions occurred. The difficulties to compare these results to historical controls are, of course, too wel1 known to merit discussion here, and obviously one cannot draw far reaching conclusions from this relatively smal1 number of patients. However, we would like to record that the response of this group of tumors to once weekly treatments seemed to be distinctly better than we had anticipated on the basis of our experience with radiotherapy with multiple fractions per week. This subjective clinical judgement must be substan-
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Fig. 4(b).
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Fig. 4(c). Fig. 4. Histological response of a malignant melanoma to once weekly treatments. (Patient 3);( a) Original biopsy: melanoma present in dermis and fat; (b) Two months post radiation; pers ;istent melanoma in dense fibrous tissue; (c) 4.5 months post radiation: abundant fibrous connective tissue with melanotic pigment but no malignant cells.
Once a week treatments 0 F. ELLIS and A. L. GOLDSON
(al
(bl
Fig. 5. Response of a malignant Schwannoma to once weekly treatments. (Patient 7 X 650 rad (1840 ret); (a) Before radiation; (b) Two months post radition.
tiated in the future by large numbers of patients, by a greater variety of tumors and if possible by prospective clinical trial. In the 35 patients treated at Memorial by this fractiohation schedule, the ret dose ranged from a low of 563 to 2190ret. Careful follow up of these 35 patients revealed mild and transient symptomatology, such as erythema, tanning, diarrhea and telangiectasia in approximately 50% of cases, but no severe morbidity or mortality attributable to radiation with 1800 ret was encountered. We admit that our follow up period is short, with maximum follow up period approaching only 2 years. DISCUSSION Radiotherapy once a week clearly is a most attractive time schedule, if it can be shown that the results are as good as those with multiple fractions per week. It permits the cancer patient who does not have to be hospitalized and who lives within commuting distance to go on without interrupting his life and work schedule and at the same time to get the medical care and supervision he needs for proper cancer management. Few cancer patients who are undergoing radiation therapy need a medical examination including blood counts more than once a week. The advantages of once a week treatments
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in some situations, that this schedule has been used on occasion by a number of radiotherapists. For instance at Ohio State University Hospita1 Henschke treated 30 patients in the years 1952-55 with 500 rad per week for a total dose of 5000 rad. (Personal Communication oral, October 1976.) These were patients from outlying farms in Ohio, who could not come or could not be brought for radiotherapy more often. The response seemed to be essentially the same as with conventional fractionation. Aristizabal’ reported from Columbia, South America that with only one cobalt machine for 3 million people, treatments of 500 rad given once a week made it possible to treat many patients, who otherwise would have gone untreated. He also stated, that at the Puerto Rico Nuclear Center, 38 cases of advanced carcinoma of the breast have been treated with once a week doses of 500 rad for a total of 5000 rad with satisfactory response.’ The most facinating implication of our data is the possibility, that at least for some tumors, once a week treatment may be better than multiple fractions per week. This possibility rarely has been considered, but it is by no means a radiobiological impossibility. It has been suggested previously by Ellis that for cells with higher extrapolation num-
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bers a smal1 number of large fractions may, for the same NSD, leave fewer survivors than wil1 the conventional 30 doses of 200rad. Moreover, it appeared that for cells with extrapolation numbers of 2, such as connective tissue a smal1 number of large fractions might have a smaller effect than the conventional30 x 200 rad. As has been shown by Ellis and Sorenson,2.3 the graphs of cel1 survival and ret are almost coincident if numbers of fractions are plotted against dose per fractions for D,, = 160 n = 2 or Do = 150 n = 2.2. In other words, a smal1 number of large dose fractions have in the NSD concept the same cell-killing effect on the normal connective tissue as conventional fractionation, but a greater cell-killing effect on cells with high extrapolation numbers, such as seem to be characteristic of resistant tumors. Conceptually it seems reasonable (if malignant cells are dividing slowly and die only as a result of radiation in subsequent mitoses), to allow time between fractions for proliferation of normal cells. Their growth may be aided by homoeostatic recovery processes and by improved oxygenation, which leave gaps in the tumor because of
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gradual autolysis of the destroyed malignant cells. In this connection, it also is interesting that recent skin erythema studies on patients by Turesson and Natter” showed that the radiation reactions of the normal skin were identical after 5 treatments per week with 235 rad each for a total of 3760rad in 16 treatments in 22 days (1400 ret) and after irradiation once a week with 675 rad for a total of 2700 rad in 4 treatments in 22 days (1400 ret). Finally, we would like to reflect, that widely different time and dose schedules have shown in clinical practice only such smal1 differences in tumor control and normal tissue damage, that no schedule has emerged, which clearly is superior. If different schedules give essentially the same results, one should pick the one which is more convenient for the patient and which permits to take care of more patients in the areas of the world, which lack radiation therapists and supervoltage machines. Once a week treatments thus could become a significant contribution to practica1 cancer management.
REFERENCES 1. Aristizabal, S.: Discussion remarks. In Proc. radiotherapy. Front. Rad. Ther., Vol. 3, ed. by Conf. on the Time-dose Relationship in CliniVaeth, J.M. Karger, Basel, 1968, pp. 131-140. cal Radiotherapy, ed. by Caldwell W.L., Tol7. Ellis, F.: Fractionation in radiotherapy. In bert D.D. Middleton, Wisconsin, Madison Modem Trends in Radiotherapy, ed. by Printing & Publishing, 1975, p. 189. Seeley, T.J., Wood, C.A. London, Butter2. Ellis, F., Sorensen, A.: A method of estimating worths, 1967, Chap. 2, pp. 34-51. biological effect of combined intracavitary low 8. Ellis, F.: Tolerante dosage in radiotherapy dose rate radiation with external in carcinoma of with 200KV X-rays. Br. J. Radiol. 15: 348, the cervix uteri. Radiology 110-681, 1974. 1942. 3. Ellis, F.: Letter: The NSD concept and 9. Regaud, C.: Influence de la duree d’irradiation Br. J. Radiol. 47 sur les effects determines dans le testicule par radioresistant tumors. (564) p. 909, 1974. le radium. Compt. Rend Sec. de Biol. 86: 7874. Ellis, F.: Nomina1 standard dose and the ret. 790, 1922. Br. J. Radiol. 44: 101-108, 1971. 10. Sugahara, T., Revesz, L., Scott, 0. (eds): 5. Ellis, F.: The relationship of biological effect Fraction Size in Radiobiology, Tokyo, Igaku to dose-time fractionation factors in radioShoin, 1973, pp. 180-187. Radiation ll. Turesson I., Notter, G.: Control of dose adtherapy. Topics in Current ministered once a week and three times a day Research, Vol. 4, ed. by Ebert, M., Howard, J. H. Amsterdam, North-Holland, 1968, Chap. 7, according to schedules calculated by the CRE formula, using skin reaction as a biological pp. 359-397. 6. Ellis, F.: Time, fractionation and dose rate in parameter. Radiology 120: 339404, 1976.
